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Frontiers in Pharmacology 2024Dilated cardiomyopathy (DCM) is a fatal myocardial condition with ventricular structural changes and functional deficits, leading to systolic dysfunction and heart...
Dilated cardiomyopathy (DCM) is a fatal myocardial condition with ventricular structural changes and functional deficits, leading to systolic dysfunction and heart failure (HF). DCM is a frequent complication in oncologic patients receiving Doxorubicin (Dox). Dox is a highly cardiotoxic drug, whereas its damaging spectrum affects most of the organs by multiple pathogenic cascades. Experimentally reproduced DCM/HF through Dox administrations has shed light on the pathogenic drivers of cardiotoxicity. Growth hormone (GH) releasing peptide 6 (GHRP-6) is a GH secretagogue with expanding and promising cardioprotective pharmacological properties. Here we examined whether GHRP-6 administration concomitant to Dox prevented the onset of DCM/HF and multiple organs damages in otherwise healthy rats. Myocardial changes were sequentially evaluated by transthoracic echocardiography. Autopsy was conducted at the end of the administration period when ventricular dilation was established. Semiquantitative histopathologic study included heart and other internal organs samples. Myocardial tissue fragments were also addressed for electron microscopy study, and characterization of the transcriptional expression ratio between Bcl-2 and Bax. Serum samples were destined for REDOX system balance assessment. GHRP-6 administration in parallel to Dox prevented myocardial fibers consumption and ventricular dilation, accounting for an effective preservation of the LV systolic function. GHRP-6 also attenuated extracardiac toxicity preserving epithelial organs integrity, inhibiting interstitial fibrosis, and ultimately reducing morbidity and mortality. Mechanistically, GHRP-6 proved to sustain cellular antioxidant defense, upregulate prosurvival gene Bcl-2, and preserve cardiomyocyte mitochondrial integrity. These evidences contribute to pave potential avenues for the clinical use of GHRP-6 in Dox-treated subjects.
PubMed: 38873418
DOI: 10.3389/fphar.2024.1402138 -
Molecular Biomedicine Jun 2024Sleep deprivation (SD) has emerged as a critical concern impacting human health, leading to significant damage to the cardiovascular system. However, the underlying...
Sleep deprivation (SD) has emerged as a critical concern impacting human health, leading to significant damage to the cardiovascular system. However, the underlying mechanisms are still unclear, and the development of targeted drugs is lagging. Here, we used mice to explore the effects of prolonged SD on cardiac structure and function. Echocardiography analysis revealed that cardiac function was significantly decreased in mice after five weeks of SD. Real-time quantitative PCR (RT-q-PCR) and Masson staining analysis showed that cardiac remodeling marker gene Anp (atrial natriuretic peptide) and fibrosis were increased, Elisa assay of serum showed that the levels of creatine kinase (CK), creatine kinase-MB (CK-MB), ANP, brain natriuretic peptide (BNP) and cardiac troponin T (cTn-T) were increased after SD, suggesting that cardiac remodeling and injury occurred. Transcript sequencing analysis indicated that genes involved in the regulation of calcium signaling pathway, dilated cardiomyopathy, and cardiac muscle contraction were changed after SD. Accordingly, Western blotting analysis demonstrated that the cardiac-contraction associated CaMKK2/AMPK/cTNI pathway was inhibited. Since our preliminary research has confirmed the vital role of Casein Kinase-2 -Interacting Protein-1 (CKIP-1, also known as PLEKHO1) in cardiac remodeling regulation. Here, we found the levels of the 3' untranslated region of Ckip-1 (Ckip-1 3'UTR) decreased, while the coding sequence of Ckip-1 (Ckip-1 CDS) remained unchanged after SD. Significantly, adenovirus-mediated overexpression of Ckip-1 3'UTR alleviated SD-induced cardiac dysfunction and remodeling by activating CaMKK2/AMPK/cTNI pathway, which proposed the therapeutic potential of Ckip-1 3'UTR in treating SD-induced heart disease.
Topics: Animals; Male; Mice; 3' Untranslated Regions; AMP-Activated Protein Kinases; Calcium-Calmodulin-Dependent Protein Kinase Kinase; Carrier Proteins; Mice, Inbred C57BL; Myocardium; Signal Transduction; Sleep Deprivation; Troponin I
PubMed: 38871861
DOI: 10.1186/s43556-024-00186-y -
Clinical Case Reports Jun 2024An interesting case that shows the importance of identifying a pathogenic TTN gene mutation through genetic assessment in unexplained cardiomyopathy, especially with...
KEY CLINICAL MESSAGE
An interesting case that shows the importance of identifying a pathogenic TTN gene mutation through genetic assessment in unexplained cardiomyopathy, especially with family history. This case highlights the need for genetic counseling and testing for at-risk relatives, and advocates for personalized management considering both genetic and lifestyle factors.
ABSTRACT
This case report examines a 33-year-old Hispanic male with bipolar disorder, schizophrenia, and a history of substance use, presenting with acute respiratory failure and cardiac arrest. The patient's nonischemic dilated cardiomyopathy (DCM) highlights the critical role of genetic factors, particularly titin gene (TTN) mutations, in cardiomyopathy pathogenesis. Through genetic analysis, we explore the intersection of lifestyle factors and genetic predisposition in DCM, underscoring the importance of comprehensive genetic testing for accurate diagnosis and targeted therapy. This case contributes to the evolving understanding of DCM etiology, emphasizing the necessity of considering both environmental and genetic factors in clinical assessment and management.
PubMed: 38868113
DOI: 10.1002/ccr3.9069 -
European Heart Journal Supplements :... Apr 2024In the ESC 2023 guidelines, cardiomyopathies are conservatively defined as 'myocardial disorders in which the heart muscle is structurally and functionally abnormal, in...
In the ESC 2023 guidelines, cardiomyopathies are conservatively defined as 'myocardial disorders in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease, and congenital heart disease sufficient to cause the observed myocardial abnormality'. They are morpho-functionally classified as hypertrophic, dilated, restrictive, and arrhythmogenic right ventricular cardiomyopathy with the addition of the left ventricular non-dilated cardiomyopathy that describes intermediate phenotypes not fulfilling standard disease definitions despite the presence of myocardial disease on cardiac imaging or tissue analysis. The new ESC guidelines provide 'a guide to the diagnostic approach to cardiomyopathies, highlight general evaluation and management issues, and signpost the reader to the relevant evidence base for the recommendations'. The recommendations and suggestions included in the document provide the tools to build up pathways tailored to specific cardiomyopathy (phenotype and cause) and define therapeutic indications, including target therapies where possible. The impact is on clinical cardiology, where disease-specific care paths can be assisted by the guidelines, and on genetics, both clinics and testing, where deep phenotyping and participated multi-disciplinary evaluation provide a unique tool for validating the pathogenicity of variants. The role of endomyocardial biopsy remains underexploited and confined to particular forms of restrictive cardiomyopathy, myocarditis, and amyloidosis. New research and development will be needed to cover the gaps between science and clinics. Finally, the opening up to disciplines such as bioinformatics, bioengineering, mathematics, and physics will support clinical cardiologists in the best governance of the novel artificial intelligence-assisted resources.
PubMed: 38867869
DOI: 10.1093/eurheartjsupp/suae002 -
Stem Cell Research Aug 2024Dilated cardiomyopathy (DCM) is one of the main causes of sudden cardiac death and heart failure and is the leading indication for cardiac transplantation worldwide....
Dilated cardiomyopathy (DCM) is one of the main causes of sudden cardiac death and heart failure and is the leading indication for cardiac transplantation worldwide. Mutations in dozens of cardiac genes have been connected to the development of DCM including the Troponin T2 gene (TNNT2). Here, we generated a human induced pluripotent stem cells (hiPSCs) from a DCM patient with a familial history that carries a missense mutation in TNNT2. The hiPSCs show typical morphology of pluripotent stem cells, expression of pluripotency markers, normal karyotype, and in vitro capacity to differentiate into all three germ layers.
Topics: Humans; Cardiomyopathy, Dilated; Induced Pluripotent Stem Cells; Troponin T; Cell Differentiation; Cell Line; Male; Karyotype
PubMed: 38861774
DOI: 10.1016/j.scr.2024.103467 -
Cureus May 2024The public health concerns from Chagas disease warrant improved cardiovascular imaging efforts, and in this report, we review a military service member presenting with...
The public health concerns from Chagas disease warrant improved cardiovascular imaging efforts, and in this report, we review a military service member presenting with electrocardiographic and cardiac magnetic resonance imaging (CMR) findings that recognized a Chagas dilated cardiomyopathy. We present an updated Chagas staging classification incorporating CMR to increase diagnosing cardiomyopathies.
PubMed: 38854227
DOI: 10.7759/cureus.59900 -
BioRxiv : the Preprint Server For... Jun 2024Cardiomyopathy, disease of the heart muscle, is a significant contributor to heart failure. The pathogenesis of cardiomyopathy is multifactorial and involves genetic,...
Cardiomyopathy, disease of the heart muscle, is a significant contributor to heart failure. The pathogenesis of cardiomyopathy is multifactorial and involves genetic, environmental, and lifestyle factors. Identifying and characterizing novel genes that contribute to cardiac pathophysiology are crucial for understanding cardiomyopathy and effective therapies. In this study, we investigated the role of a novel gene, ( ), in cardiac pathophysiology using a cardiac-specific knockout mouse model as well as a Drosophila model. Our previous work demonstrated that OLA1 modulates the hypertrophic response of cardiomyocytes through the GSK-beta/beta-catenin signaling pathway. Furthermore, recent studies have suggested that OLA1 plays a critical role in organismal growth and development. For example, null mice exhibit increased heart size and growth retardation. It is not known, however, if loss of function for leads to dilated cardiomyopathy. We generated cardiac-specific knockout mice (OLA1-cKO) to evaluate the role of OLA1 in cardiac pathophysiology. We found that -cKO in mice leads to dilated cardiomyopathy (DCM) and left ventricular (LV) dysfunction. These mice developed severe LV dilatation, thinning of the LV wall, reduced LV function, and, in some cases, ventricular wall rupture and death. In Drosophila, RNAi-mediated knock-down specifically in developing heart cells led to the change in the structure of pericardial cells from round to elongated, and abnormal heart function. This also caused significant growth reduction and pupal lethality. Thus, our findings suggest that OLA1 is critical for cardiac homeostasis and that its deficiency leads to dilated cardiomyopathy and dysfunction. Furthermore, our study highlights the potential of the gene as a therapeutic target for dilated cardiomyopathy and heart failure.
PubMed: 38854005
DOI: 10.1101/2024.05.28.596265 -
Communications Biology Jun 2024The Drosophila model is pivotal in deciphering the pathophysiological underpinnings of various human ailments, notably aging and cardiovascular diseases. Cutting-edge...
The Drosophila model is pivotal in deciphering the pathophysiological underpinnings of various human ailments, notably aging and cardiovascular diseases. Cutting-edge imaging techniques and physiology yield vast high-resolution videos, demanding advanced analysis methods. Our platform leverages deep learning to segment optical microscopy images of Drosophila hearts, enabling the quantification of cardiac parameters in aging and dilated cardiomyopathy (DCM). Validation using experimental datasets confirms the efficacy of our aging model. We employ two innovative approaches deep-learning video classification and machine-learning based on cardiac parameters to predict fly aging, achieving accuracies of 83.3% (AUC 0.90) and 79.1%, (AUC 0.87) respectively. Moreover, we extend our deep-learning methodology to assess cardiac dysfunction associated with the knock-down of oxoglutarate dehydrogenase (OGDH), revealing its potential in studying DCM. This versatile approach promises accelerated cardiac assays for modeling various human diseases in Drosophila and holds promise for application in animal and human cardiac physiology under diverse conditions.
Topics: Animals; Cardiomyopathy, Dilated; Aging; Disease Models, Animal; Machine Learning; Drosophila melanogaster; Deep Learning; Heart; Humans; Drosophila
PubMed: 38849449
DOI: 10.1038/s42003-024-06371-7 -
Circulation. Heart Failure Jun 2024The immune systems and chronic inflammation are implicated in the pathogenesis of dilated cardiomyopathy (DCM) and heart failure. However, the significance of neutrophil...
BACKGROUND
The immune systems and chronic inflammation are implicated in the pathogenesis of dilated cardiomyopathy (DCM) and heart failure. However, the significance of neutrophil extracellular traps (NETs) in heart failure remains to be elucidated.
METHODS
We enrolled consecutive 62 patients with heart failure with idiopathic DCM who underwent endomyocardial biopsy. Biopsy specimens were subjected to fluorescent immunostaining to detect NETs, and clinical and outcome data were collected. Ex vivo and in vivo experiments were conducted.
RESULTS
The numbers of NETs per myocardial tissue area and the proportion of NETs per neutrophil were significantly higher in patients with DCM compared with non-DCM control subjects without heart failure, and the numbers of NETs were negatively correlated with left ventricular ejection fraction. Patients with DCM with NETs (n=32) showed lower left ventricular ejection fraction and higher BNP (B-type natriuretic peptide) than those without NETs (n=30). In a multivariable Cox proportional hazard model, the presence of NETs was independently associated with an increased risk of adverse cardiac events in patients with DCM. To understand specific underlying mechanisms, extracellular flux analysis in ex vivo revealed that NETs-containing conditioned medium from wild-type neutrophils or purified NET components led to impaired mitochondrial oxygen consumption of cardiomyocytes, while these effects were abolished when PAD4 (peptidyl arginine deiminase 4) in neutrophils was genetically ablated. In a murine model of pressure overload, NETs in myocardial tissue were predominantly detected in the acute phase and persisted throughout the ongoing stress. Four weeks after transverse aortic constriction, left ventricular ejection fraction was reduced in wild-type mice, whereas PAD4-deficient mice displayed preserved left ventricular ejection fraction without inducing NET formation.
CONCLUSIONS
NETs in myocardial tissue contribute to cardiac dysfunction and adverse outcomes in patients with heart failure with DCM, potentially through mitochondrial dysfunction of cardiomyocytes.
Topics: Cardiomyopathy, Dilated; Humans; Extracellular Traps; Heart Failure; Male; Female; Middle Aged; Animals; Myocardium; Neutrophils; Stroke Volume; Myocytes, Cardiac; Ventricular Function, Left; Mice; Aged; Mitochondria, Heart; Mice, Inbred C57BL; Biopsy
PubMed: 38847093
DOI: 10.1161/CIRCHEARTFAILURE.123.011057